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Doxycycline: Side Effects

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See also Tetracyclines

Doxycycline and minocycline are more lipophilic tetracyclines. They are well absorbed after oral administration. Their half-lives are 16-18 hours. Their higher affinity for fatty tissues improves their effectiveness and changes their adverse effects profile. Local gastrointestinal irritation and disturbance of the intestinal bacterial flora occur less often than with the more hydrophilic drugs, which have to be given in higher oral doses for sufficient absorption.

Nevertheless, their toxic effects are similar to those of other tetracyclines and arise from accumulation in fatty tissues. Accumulation in a third compartment and the resulting long half-life may contribute to an increased incidence of various toxic adverse effects during long-term treatment, even if lower daily doses are used. This seems also to be the case for pigmentation disorders and possibly for neurological disturbances.

Minocycline and doxycycline are predominantly eliminated by the liver and biliary tract (70-90%). Therefore, no change in dose is needed in patients with impaired renal function. However, it should be considered that hepatic elimination of doxycycline or minocycline might be accelerated by co-administration of agents that induce hepatic enzymes.

Organs and Systems

Nervous system

Peripheral neuropathy from doxycycline has been reported.

• A 61-year-old doctor with recurrent bronchopneumonia took two courses of doxycycline. During the first course he had persistent numbness in his feet. During the second course, a few months later, he noticed after only 2 or 3 days that the numbness accelerated markedly and was associated with a low threshold for muscle cramps in the feet. He stopped taking doxycycline and during the following weeks noticed slight improvement. However, some symptoms persisted and he had neurological investigations. A wide range of clinical and laboratory tests showed no cause for his neuropathy.

A search for an association between doxycycline and polyneuropathy failed to identify any documented cases. An inquiry to the Swedish Adverse Drug Reactions Advisory Committee elicited information about three cases of “paresthesia,” two cases of “sensitivity disturbance,” and one case of “neuropathy.” The last was a man who had had pain and paresthesia in the feet, arms, and face after taking doxycycline 100 mg/day for 2 weeks for prostatitis. The symptoms began to wane 1 week after treatment was stopped, and disappeared completely 1 week later.

Metabolism

Doxycycline can cause hypoglycemia.

A 70-year-old man with type 2 diabetes mellitus presented with sudden confusion, which rapidly progressed to loss of consciousness. The only drug he had taken during the previous 2 months was doxycycline (100 mg/day), which he had taken for 5 days for an upper respiratory tract infection. Urine tests for sulfonylureas were negative. Routine hematological and biochemical tests and an electrocardiogram were normal. He improved with intravenous glucose and withdrawal of doxycycline and had no further episodes of hypoglycemia over the next 3 months.

Plasma insulin was not measured in this case, so the mechanism of hypoglycemia was unclear.

Hypoglycemia has also been attributed to doxycycline in a non-diabetic patient.

Gastrointestinal

Esophageal ulcers have been described in association with oral doxycycline or tetracycline. Acute onset of substernal burning pain and dysphagia was noted within hours of taking the drug. Remaining parts of the ingested capsule were identified by esophagoscopy.

Thirty centers for pharmacovigilance in France have reported 81 cases of esophageal damage after treatment with tetracyclines collected between 1985 and 1992. There were 64 ulcers, eight cases of dysphagia, and nine of esophagitis. Most (96%) of the cases were caused by doxycycline and 73% of the patients were female, mean age 29 years. Prescriptions were for dermatological (54%), urogenital (23%), and ENT diseases. In one patient, a 71-year-old man, an esophagobronchial fistulation required esophagectomy. In 92% the drugs were not taken correctly, that is at bedtime or without a sufficient quantity of fluid. Treatment with sucralfate lg tds did not change the outcome of tetracycline-induced esophageal ulcers.

Two cases of esophagitis in children have been reported.

A 12-year-old boy developed lower chest pain, having taken doxycycline for 7 days for presumed epididymitis. He had a normal chest X-ray and electrocardiogram and no signs of infection. Doxycycline was withdrawn, but the chest pain persisted. After 4 days endoscopy showed two very large ulcerated craters measuring about 5 x 12 mm in the distal esophagus.

A 15-year-old girl developed chest pain and difficulty in swallowing after having taken five doses of doxycycline. Physical examination was normal and she had a normal chest X-ray and electrocardiogram. Doxycycline was withdrawn and she was given sucralfate 10 ml tds, omeprazole having been ineffective. Gastroscopy was not performed. Her pain began to improve 2 days later.

The authors stated that it is important to inquire about the use of tetracyclines in children with chest pain, and to consider them as a possible cause of the pain.

Esophageal ulceration occurred in two adults taking doxycycline as malaria chemoprophylaxis.

A 20-year-old woman, who had been taking doxycycline malaria prophylaxis, took a doxycycline capsule (dose not given) before going to bed and awoke hours later with the feeling that the capsule was stuck in her esophagus. Over the next 4 days she developed worsening dysphagia. Esophagoscopy showed an esophageal ulcer over 20% of the esophageal surface. She was treated with ranitidine and sucralfate and improved over the next 2 days.

A 27-year-old man with an 8-day history of dysphagia and retrosternal pain was taking doxycycline prophylaxis and occasional terfenadine (doses not stated). He recalled no problems with taking any of his doxycycline prophylaxis. He had an esophagoscopy, which showed a 1 cm esophageal ulcer. He improved with ranitidine.

Liver

Doxycycline-induced liver injury has been reported. The patient took oral doxycycline 200mg/day for 8 days and had markedly altered liver function. The liver enzyme activities normalized only 109 days after withdrawal.

Fixed drug eruptions have been attributed to doxycycline.

Immunologic

Renal small-vessel vasculitis related to doxycycline has been reported.

Second-Generation Effects Teratogenicity

Doxycycline has not been shown to be teratogenic.

Susceptibility Factors

Renal disease

Doxycycline is almost completely eliminated via the liver and the biliary tract and is therefore safe in patients with pre-existing renal insufficiency. However, for intravenous administration, doxycycline is solubilized with polyvinyl-pyrrolidone, the clearance of which is less than that of doxycycline. In patients with a serum creatinine concentration of more than 250 µmol/l (3 mg/dl), it is therefore advisable to limit the duration of treatment to a few days.

Drug Administration

Drug administration route

When intravenous tetracycline became no longer available, many centers began to use doxycycline as a sclerosant. In one review, chest pain was the most frequent adverse event with doxycycline, occurring in about 40% of the 60 patients in whom it had been used, and fever occurred in about 7%. In a more recent controlled trial in 106 patients treated with either doxycycline or bleomycin, there was chest pain in 20% of the patients treated with doxycycline, and nausea in one patient.

Drug-Drug Interactions

Methotrexate

Doxycycline can be added to the long list of drugs that can interact with methotrexate.

A 17-year-old girl with a femoral osteosarcoma received her 11th cycle of methotrexate and simultaneously oral doxycycline 100 mg bd for a palpebral abscess. As in previous cycles, pharmacokinetic monitoring of methotrexate was performed. On this occasion the half-life of methotrexate was more than doubled. She developed hematological and gastroenterological toxicity.

The authors recommended that in patients receiving methotrexate an alternative to doxycycline should be used.

Warfarin

There has been a report of bleeding and prolonged international normalized ratio in a 69-year-old man given warfarin and doxycycline.

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